The FP prostaglandin receptor belongs to a family of prostaglandin receptors, all of which have seven-transmembrane domains and couple to specific G-proteins. When activated by the binding of a specific ligand (a prostaglandin belonging to one of several defined classes of prostaglandins) the G-proteins transmit and amplify within the cell a signal to their preferred prostaglandin receptors on the surface of the cell membrane. (Coleman et al., VIII International Union of Pharmacology classification of prostanoid receptors; Properties, distribution, and structure of the receptors and their subtypes, Pharmacol. Rev.,]46:205-229 (94)). Ligand-induced activation of the FP prostaglandin receptor is believed to involve activation of the enzyme phospholipase C (mediated by specific G-proteins), resulting in rapid hydrolysis of phosphatidylinositol 4,5-bisphosphate in the cell membrane. The products of this hydrolysis are inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), which act as second messengers inside the cell. (Coleman et al., VIII International Union of Pharmacology classification of prostanoid receptors: Properties, distribution, and structure of the receptors and their subtypes, Pharmacol. Rev., 46:205-229 (1994); Berridge, Inositol trisphosphate and calcium signalling Nature 361:315-325 (1993); Davis et al., Prostaglandin F2xcex1 stimulates phosphatidylinositol 4,5-bisphosphate hydrolysis and mobilizes intracellular Ca2+ in bovine luteal cells, Proc. Natl. Acad. Sci., (USA) 84:3728-3732 (1987); Nakao et al., Characterization of prostaglandin F2xcex1 receptor of mouse 3T3fibroblasts and its functional expression in Xenopus laevis oocytes, J. Cell. Physiol., 155:257-264 (1993); and Griffin et al., FP prostaglandin receptors mediating inositol phosphates generation and calcium mobilization in Swiss 3T3 Cells: A pharmacological study, J. Pharmacol. Exp. Ther., 281: 845-854 (1997)). IP3 mobilizes Ca++ from intracellular stores and DAG activates protein kinase C. Together these second messengers activate various enzymes and other proteins to produce the final biological responses. The latter may involve tissue contraction, hormone release, fluid secretion, or initiation of an inflammatory response.
Like most prostaglandin receptors, the FP prostaglandin receptor is broadly distributed in human and animal tissues. Various endogenous prostaglandins, arising from the action of cyclooxygenases on arachidonic acid, can bind to and activate the FP receptor, with prostaglandin F2xcex1 (PGF2xcex1) being the most potent FP agonist of these endogenous ligands. Therapeutic applications of FP receptor activation using such endogenous prostaglandins are known. (Coleman et al., Prostanoids and their receptors, in Comprehensive Medicinal Chemistry: The Rational Design, Mechanistic Study and Therapeutic Application of Chemical Compounds (Hansch, C., Sammes, P. G., Taylor, J. B., Eds.) (Pergamon Press: New York, (Oxford)) 3:674 (1990); and Coleman et al., VIII International Union of Pharmacology classification of prostanoid receptors: Properties, distribution, and structure of the receptors and their subtypes, Pharmacol. Rev., 46:205-229 (1994)).
Characterization of the functions of the various prostaglandin receptors has been advanced by the availability of synthetic analogs of the endogenous prostaglandins. Many such analogs have been prepared and described in the literature. (Coleman et al., Prostanoids and their receptors, in Comprehensive Medicinal Chemistry: The Rational Design, Mechanistic Study and Therapeutic Application of Chemical Compounds (Hansch, C., Sammes, P. G., Taylor, J. B., Eds.) (Pergamon Press: New York, (Oxford)) 3:674 (1990).
In general, rational design of structural analogs of the endogenous prostaglandins based on empirically-derived structure-activity relationships has resulted in more potent and more selective agonists at the various prostaglandin receptors. The availability of well-characterized potent and selective agonists at the FP and other prostaglandin receptors has increased understanding of the in vivo pharmacological (and potential therapeutic) actions of both the specific prostaglandin analogs and the specific prostaglandin receptors to which they bind. However, it has now been discovered that potent and selective prostaglandin receptor antagonists serve a complementary function in defining the physiologic and pharmacological roles of prostaglandin receptors, and in certain instances are themselves valuable therapeutic agents.
There are only a few classes of prostaglandin receptors for which antagonists with defined chemical structures and well-characterized antagonistic biological activities have been identified. (Coleman et al., VIII International Union of Pharmacology classification of prostanoid receptors: Properties, distribution, and structure of the receptors and their subtypes, Pharmacol. Rev., 46:205-229 (1994)). For the FP receptor, compounds suggested to be or classified as antagonists include the dimethylamide and dimethylamine of PGF2xcex1 (Maddox et al., Amide and i-i amino derivatives of F prostaglandins as prostaglandin antagonists, Nature, 273:549-552 (1978); (Fitzpatrick et al., Antagonism of the pulmonary vasoconstrictor response to prostaglandin F2xcex1 by N-dimethylamino substitution of prostaglandin F2xcex1 J. Pharmacol. Exp. Ther., 206:139-142 (1978)) phloretin (Kitanaka et al., Phloretin as an antagonist of prostaglandin F2xcex1 receptor in cultured rat astrocytes, J. Neurochem., 60:704-708 (1993)), glybenclamide and tolbutamide (Delaey and Van de Voorde, Prostanoid-induced contractions are blocked by sulfonylureas, Eur. J. Pharmacol., 280:179-184 (1995)). Most of these compounds, however, are either inactive or very weak FP prostaglandin receptor antagonists with little or no selectivity at the FP prostaglandin receptor.
There remains a need, therefore, for potent and selective antagonists of the FP prostaglandin receptor that can be used for the general purposes of: 1) defining more precisely the function(s) of the FP prostaglandin receptor and its selective agonists in vivo and in vitro (e.g., as valuable pharmacological tools); 2) serving as a diagnostic tool for FP prostaglandin receptor function in various disease processes; 3) treating various conditions, diseases or untoward effects associated with FP receptor activation, such as ocular hyperemia, cystoid macular edema, iris hyperpigmentation or melanogenesis, excessive bone deposition, and premature labor.
The present invention is directed to the use of certain 11xcex2-fluoro-15xcex2-hydroxy PGF2xcex1 analogs to antagonize FP receptor-mediated biological responses.